N-acyl-(piperazinoalkyl)-pyrazoles

ABSTRACT

N-acyl-pyrazoles of the formula   WHEREIN A is alkylene of one to four carbon atoms; Ar is phenyl, unsubstituted or substituted by one or more of alkyl and alkoxy of one to four carbon atoms, trifluoromethyl and halogen, and Q is   R being saturated or unsaturated alkyl or aralkyl of up to 10 carbon atoms, aryl of up to 10 carbon atoms, unsubstituted or substituted by one or more of alkyl, of 1-4 carbon atoms, amino and methoxy, -NH2, -N(CH3)2 or alkoxy of 1-4 carbon atoms, and the physiologically acceptable salts thereof, possess valuable pharmacological properties, especially CNS-depressive activity, e.g., one or more of narcosis-prolonging, tranquilizing and neuroleptic properties.

United States Patent 1 Borck et al.

1 Oct. 1, 1974 [73] Assignee: Merck Patent Gesellschaft mit beschrankter Haftung, Darrnstadt, Germany [22] Filed: Mar. 3, 1972 [21] Appl. No.: 231,750

[30] Foreign Application Priority Data Mar. 5 1971 Germany 2110568 [52] US. Cl 260/268 PH, 260/240 K, 424/250 [51] Int. Cl C07d 51/70 [58] Field of Search 260/268 PH, 268 H, 310 R [56] References Cited UNITED STATES PATENTS 3,224,217 2/1960 Schmidt 260/208 H 3,308,130 3/1962 260/310 R 3,367,936 2/1968 Koppe et al 260/268 H 3,428,032 11/1969 260/268 PH 3,470,184 9/1969 260/268 PH 3,491,097 1/1970 260/268 PH 3,649,631 3/1972 Koppe 260/268 H Primary Examiner-Donald G. Daus Attorney, Agent, or Firm-Mi1len, Raptes & White [57] ABSTRACT N-acyl-pyrazoles of the formula Q-A-N N-Ar wherein A is alkylene of one to four carbon atoms; Ar is phenyl, unsubstituted or substituted by one or more of alkyl and alkoxy of one to four carbon atoms, trifluoromethyl and halogen, and Q is O! N l N-COR on N/ on, \N/

17 Claims, No Drawings 1 N-ACYL-( PIPERAZINOALKYL)-PYRAZOI.ES

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION The novel compounds of this invention are N-acyl- (piperazinoalkyl)-pyrazoles of the Formula I wherein A is branched or straight chain alkylene of one to four carbon atoms, Ar is phenyl, unsubstituted or substituted by one or more of alkyl and alkoxy, each of one to four carbon atoms, trifluoromethyl and halogen,

Qis

and R is saturated or unsaturated alkyl or aralkyl, each of up to carbon atoms, aryl of up to 10 carbon atoms, unsubstituted or substituted by one or more of alkyl of one to four carbon atoms, amino and methoxy, Nll N(CI-I or alkoxy of up to four carbon atoms, and the physiologically acceptable acid addition salts thereof, and mixtures thereof. These compounds possess valuable pharmacological properties with good compatibility, including CNS-depressive activity, e.g., one or more of narcosis-prolonging, narcosispotentiating, tranquilizing and neuroleptic activity. Other properties are blood pressure lowering, noradrenaline-potentiating or adrenaline-potentiating, stimulating, e.g., thymoanaleptic and tetrabenazineantagonistic, and antihistaminic and bronchospasmolytic properties. Accordingly, the novel compounds of this invention can be employed as drugs. They are also useful as intermediates for the preparation of other drugs.

The compounds of Formula I and the physiologically acceptable salts thereof can be produced by the following processes:

a a compound of Formula [I v. o\ Wm.--

CH3COCHzCOA-N N-Ar H is reacted with a compound of the formula RCO- NHNH (Ill);

b. a compound of Formula IV QiA-N NAr wherein O is cmlN or cir3i H is reacted with an acid of the formula RCOOI-I (V); or a functional derivative thereof;

c. a compound of the formula Q A X (VI) wherein X is an optionally reactively esterified OH-group, is reacted with a compound of Formula VII and/or a compound of Formula I is converted into a physiologically acceptable salt thereof by treatment with an acid and/or liberated from an acid addition salt thereof by treatment with a base.

In Formulae 11 through VII, A, Ar, Q, Q R, and X each have the values given above.

Of the compounds of Formula I, preferred are wherein A is straight chain alkylene of one to four carbon atoms. A thus preferably is (CH e.g., CH CI-I CH CH Cl-l Cl-I or CH CH CH Ch- However, A can also be, e.g., CH(CH Cl-I(Cl-l ',)CI-l -CH CH(CH Ar in each instance preferably is unsubstituted phenyl or phenyl mono-, dior trisubstituted by one or more of alkyl of one to four carbon atoms, e.g., methyl, ethyl and isopropyl, alkoxy or one to four, carbon atoms, e.g., methoxy, ethoxy, trifluoromethyl or halo, e.g., phenyl, 0-, m-, and ptolyl, 2,4-dimethylphenyl, o-, 'm-, and p-ethylphenyl, p-isopropylphenyl, 2-methyl-5-isopropylphenyl, o-, mand pmethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5- t'rimethoxyphenyl, 2-methoxy-5-methylphenyl, o-, mand p-ethoxyphenyl, o-, m-and p-trifluoromethylphenyl, o-, mand p-fluorophenyl, o-, mand pchlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- dichlorophenyl, 2,4,6-trichlorophenyl, o-, mand pbromophenyl, 2,4-dibromophenyl, o-, mand piodophenyl.

R, when optionally unsaturated alkyl, preferably is n-alkyl of one to 10 carbon atoms, e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. R can also be, e.g., isopropyl, isobutyl, sec.-butyl, tert,-buty1, isoamyl, isohexyl, ethenyl and ethinyl; when R is optionally unsaturated aralkyl of up to 10 carbon atoms, R can be, e.g., benzyl, aand B-phenethyl, 3-phenyl-1-propyl, 2-phenyll -propyl, l-phenyl-l-propyl, 4-phenyl-1-butyl, styryl and phenylethinyl. Examples of R when aryl optionally mono or polysubstituted by alkyl, amino, or methoxy groups, are phenyl, naphthyl, o-, mand p-tolyl, 2,4- dimethylphenyl, o-, mand p-ethylphenyl, isopropylphenyl, 2-methyl-S-isopropylphenyl, o-, mand p-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-

trimethoxyphenyl, 2-methoxy-5-methylphenyl, paminophenyl, or p-dimethylaminophenyl. When R is alkoxy of up to four carbon atoms e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.- butoxy, or tert,-butoxy, the compound is a carbalkoxy substituted pyrazole. When R is NI-I or -N(CI-l the resulting compound is an amide substituted pyrazole.

In the definition of X, the term reactively esterified OH-groups means an ester which can be substituted by amino-nitrogen when reacted with an amine, preferably, acyloxy, e.g., acetoxy, or other alkanoyloxy of one to four carbon atoms, methanesulfonyloxy or other alkanesulfonoxy of one to four carbon atoms, p-

' toluenesulfonyloxy or other arylsulfonyloxy of six to carbon atoms, and mineral acid esters, e.g., Cl, Br, or I.

As stated above, certain type of compounds of Formula I are preferred, e.g., those wherein:

a. A is straight chain alkylene, especially ethylene;

b. Ar is phenyl, preferably mono-substituted phenyl, more preferably those wherein the substituent is halo, preferably Cl, or alkyl of one to four carbon atoms, preferably CH especially those of (a) above;

c. R is straight-chain alkyl, dialkyla'mine, preferably dimethylamino, alkoxy, preferably ethoxy, phenyl,

preferably aminoor alkoxy-substituted phenyl, preferably methoxy-substituted phenyl, or styryl, alkoxy in each instance containing one to four carbon atoms, especially those of (a) and (b) above.

Starting compounds of Formula II are preferably 1- (N '-arylpiperazino)-2,4-pentanediones wherein aryl has the values given above, and the corresponding -3,5- hexanediones, -4,6-heptanediones and -5,7- octanediones.

The starting compounds of Formula II can be obtained, for example, by reacting a 1,3-dicarbonyl compound halogenated in the terminal position, e.g., 1- bromoor l-chloro-pentanedione-(2,4), with an arylpiperazine of Formula VII.

Examples of starting compounds of Formula [II are aliphatic, araliphatic and aromatic acylhydazines, e.g., acetyl-, propinyl-, butyryl-, isobutyryl-, valeryol-, isovaleryl-, hexanoyl-, heptanoyl-, octanoyl, nonanoyl-, acryloyl-, propioloyl-, phenyIacetyl-, cinnamoyl-, benzoyl-, naphthoyl-, o-, m-, and p-toluoyl, 3,4,5-trimethoxybenzoyl-, p-aminobenzoyland pdimethylaminobenzoylhydrazine. It is also possible, for example, to employ functionally modified carbonic acid hydrazides, e.g., semi-carbazide.

The acylhydrazines of Formula III are obtained, for

example, from the corresponding carboxylic acid esters and hydrazine hydrate.

The starting compounds of Formula IV are preferably 3(5)-[(N'-arylpiperazino)-ethyl]-5(3)- methylpyrazoles, wherein Ar has the values given above, e.g., m-chlor'ophenyl and m-tolyl. The corresponding -methyl]-5(3)-methyl-, propyl]-5(3 )-methyl-, and -butyl]-5(3)-methylpyrazoles wherein the alkyl groups are branched or straight chains can also be employed.

Compounds of Formula IV are known or can be produced, for example, by reacting a pyrazole of the formula Q,-A-X With a piperazine of the Formula VII or by other conventional methods.

aliphatic carboxylic acids of up to II carbon atoms, and unsubstituted or optionally substituted aromatic carboxylic acids of up to 11 carbon atoms. Functional derivatives of these carboxylic acids are preferably the halogenides thereof, preferably acid bromides and acid chlorides, esters thereof, preferably of alkanols of one to four carbon atoms, anhydrides, including mixed anhydrides of carboxylic acids and carbonic acid monoesters, ketenes, and carbonic acid derivatives, of which chloroformic acid esters are particularly suitable.

As the starting compounds of Formula VI, especially suitable are the l-acyl-S-methyl derivatives of 3- chloromethyl-, 3-( l-chloroethyl)-, 3-( 2-chloroethyl)-, 3-(3-chloropropyI)-, or 3-(4-chlorobutyl)-pyrazole, and/or the l-acyl-3-methyl derivatives of 5- chloromethyl-, 5-(l-chloroethyl)-, 5-(2-chloroethyl)-, 5-(3-chloropropyl)- and 5-( 4-chlorobutyl)-pyrazole, as well as the corresponding 3-bromoalkyl, 3-iodoalkyl, 5-bromoalkyl and 5-iodoalkyl compounds, and the esters of the corresponding l-acyl-5-methyl-3- hydroxyalkyland/or l-acyI-3-methyl-5-hydroxyalkyl- Examples of acids of Formula V are aliphatic carboxylic acids of one to l 1 carbon atoms, carbonic acid, ar-

pyrazoles, in particular the methaneand p-toluenesulfonates thereof.

Compounds of Formula VI are known or can be easily prepared analogously to known compounds. For example, S-methylpyrazole-3-carboxylic acid esters can be reduced catalytically or with lithium aluminum hydride to 3-hydroxymethyl-Smethylpyrazole. 2 -I-lydroxy-5-methyl-4-pyrone can be converted with hydrazine to 5-methyI-pyrazole-3-acetic acid hydrazide, from which the corresponding esters can be obtained by alcoholy'sis. By the reduction of these esters, 3-(2- hydroxyethyl)-5-methylpyrazole can be obtained. 3-( 3- Hyclroxprobl)- and/or 3-(4-hydroxybutyl)-5- methylpyrazoles (VI, X OH, A C l-I or C I-I can be produced by condensing carbonyl compounds R-- CO-CI-I with y-butyrolactone or 'd-valerolactone, respectively, to 2-hydroxy-2-acylmethyltetrahydrofurans and -pyrans and subsequent reaction with hydrazine. The corresponding halogen compounds (VI, X Cl, Br or I) are obtained from the thus-produced alcohols with, for example, thionyl chloride, hydrobromic acid, or hydriodic acid. The corresponding acylates and sulfonic acid esters are obtained by customary esterification, for example with an acid anhydride or halogenide, e.g., acetic anhydride, methaneand p-toluenesulfonyl chloride. By the acylation of the thus-obtained products, the starting compounds of Formula VI are produced.

Of the compounds of Formula VII, the following piperazines are preferred: N-Phenyl-, N-o-to1yl-, N-mtolyl-, N-p-tolyl, N -p-ethylphe nyl-, N-omethoxyphenyl-, N-p-methoxyphenyl-, N-pmethoxyphenyl-, N-o-trifluoromethylphenyl-, N-m-trifluoromethyphenyl-, N-p-trifluoromethylphenyl-, N-ofluorophenyl-, N-m-fluorophenyl-, N-p-fluorophenyl-, N-o-chlorophenyl-, N-m-chlorophenyl-, N-pchlorophenyl-, N-o-bromophenyl-, N-m-bromophenyl-, N-p-bromophenyl-, N-o-iodophenyl-, N-m-iodophenyland N-p-iodophenylpiperazine.

The piperazines of Formula VII are known or can be obtained by reacting amines of the formula ArNI-I with diethanolamine, morpholine, or bis(2-chloroethyl) amine, or by the reaction of piperazine with a halogenide of the formula ArX wherein X is preferably is Br.

Examples of other compounds of Formula I in addition to those named hereinafter are:

l-acetyl-3(5 H N -o-chlorophenylpiperazino)- methyl]-5(3)-methylpyrazole, I

1aeemstsfl m acmifishehylpiiaiazinay Mm ethyl]-5 3 )-methylpyrazole,

l-acetyl-3(5 3-(N -o-chlorophenylpiperazino prpyl]-5(3)-methylpyrazole, 1-acetyl-3(5)-[4-(N'-o-chlorophenylpiperazino)- butyl]-(3)-methylpyrazole,

l-butyryl-3 5 H N-m-chlorophenylpiperazino methyl]-5 3 )-methylpyrazole,

l-butyryl-3 5 3-( N '-m-chlorophenylpiperazino p-ropyl]-5 3 )-methylpyrazole,

l-butyryl-3(5 )-[4-( N -m-chlorophenylpiperazino)- butyI]-5 3 )-methylpyrazole,

l-butyryl-3 5 N '-m-tolylpiperazino )-methyl]- 5 3 )-methylpyrazole,

l-butyryl-3 5 3-(N -m-tolylpiperazino )-propyl]- 5 3 )-methylpyrazole, l-butyryl-3(5)-[4-(N-m-tolylpiperazino)-butyl1- 5 3 )-methylpyrazole,

In the description which follows, the term ordinary solvent means an inert solvent suitable for that reaction, e.g., water; a hydrocarbon, e.g., heptane, cyclohexane, benzene and toluene; a halogenated hydrocarbon, e.g., chloroform, ethylene chloride, hexachlorobutadiene and chlorobenzene; an alcohol, e.g., methanol, ethanol, ethylene glycol monoethyl ether, and tert.-butyl alcohol; an ether, e.g., diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane; a ketone, e.g., acetone, butanone and acetophenone; an ester, e.g., ethyl acetate; an aprotic-dipolar solvent, e.g., dimethylformamide, acetonitrile, dimethyl sulfoxide, tetramethylurea, tetrahydrothiophene l,l-dioxide propylene carbonate and hcxamethylphosphoric triamide; or a mixture of these solvents. The terms basic catalysts and acidneutralizing agents in the following description, mean bases or basic salts, preferably hydroxides, e.g., NaOl-I, KOl-l, Ca(OH)- or Ba(OH) carbonates, such as Na CO KHCO CaCO- acetates, such as sodium acetate; or organic bases, such as triethylamine, dimethylaniline, pyridine and quinoline.

The reaction of a compound II with a compound III is preferably effected in an ordinary solvent.

It is also possible to conduct the reaction in the presence of a catalyst, preferably an acidic catalyst, e.g., mineral acids, including HCl and H 50 Lewis acids, e.g., BF and AICL, and organic acids, e.g., p-toluenesulfonic acid, acetic acid and trifluoroacetic acid. The reaction temperature can range between -l0 C. and 120 C., preferably between 0 and 100 C., preferably the boiling temperature of the solvent employed.

The acylation of a compound of Formula IV with an acid of Formula V or preferably a functional derivative thereof to obtain a compound of Formula I is accomplished in accordance with the methods described in the literature under a great variety of reaction conditions, which conditions vary with the acylating agent employed. If an acyl halogenide, preferably an acyl chloride or bromide, is employed, the reaction advantageously is conducted in solution and/or suspension. One of the ordinary solvents, inert with respect toacylating agents, is used, in most cases in the presence of a basic catalyst. The reaction temperature can range between 20 C. and +l00 C., preferably between 5 C. and +40 C. It is especially advantageous to operate under anhydrous conditions and to add, for example, the acyl halogenide at 0 C. to an anhydrous solution of the pyrazole in pyridine, in a dropwise manner. The reaction times vary between 1 hour and 4 days.

If an acid anhydride is used as the acylating agent, it is possible in most cases to conduct the reaction under the above-described reaction conditions. However, it is also possible, for example, to acylate a hydrochloride of the pyrazole employed with the acid anhydride after adding the stoichiometric amount of sodium acetate, in an aqueous solution or suspension at e,g., 40-60 C. When an excess of the acid anhydride is used as the solvent, the reaction is often accelerated by adding a small amount of concentrated H SO The acylation can also be effected with esters, preferably methyl esters, of acids of Formula V. An excess of the ester is employed, optionally with the addition of one of the ordinary solvents. The reaction temperature preferably is between -20 C. and 100 C.

If a ketene is used as the acylating agent, it is likewise possible to conduct the reaction under the abovedescribed conditions. For example, the ketene can be added dropwise under ice cooling to an aqueous sus pension of the pyrazole. However, it is more advantageous to acylate in an organic solvent at an elevated temperature, e.g., by adding the ketene dropwise to a boiling solution of the pyrazole in ethylene chloride.

The reactions of the compounds of Formulae VI and VII are effected in accordance with methods known in the literature for the alkylation of amines. The reaction is conducted, for example, in one of the ordinary solvents, optionally with the addition of an acidneutralizing agent or an excess of the compound of Formula VII. Depending on the conditions employed, the reaction times range between several minutes and 14 days. Sometimes, heating for 12-24 hours is necessary in order to attain satisfactory yields. The reaction temperature is between 0 and 200C, ordinarily at 80-130 C.

In some of the aforedescribed reactions, two position isomers can be produced which differ by the position of the double bonds and the N-acyl group in the pyrazole ring, which isomers are compounds of Formula la and lb, respectively:

A-N N-Ar A-N N-Ar [IT I N NOOR 3 III/ CH3""\N/ COR Ia Ib The formation of a mixture of these isomers, which like the pure isomers, are part of the subject matter of the present invention, is to be expected. In particular, such a mixture can be produced in the reaction of a compound of Formula II with a compound of Formula III and in acylation of a pyrazole of Formula IV with an acid of Formula V, or one of the functional derivatives thereof. If the compounds of Formula I are obtained by reacting compounds of Formula VI with compounds of Formula VII, mixtures of isomers can also be expected insofar as the starting compounds of Formula Vl already are in the form of such a mixture.

The pure isomers of Formula Ia or lb, respectively, can also be converted into each other by heating, wherein the isomer which is thermodynamically more stable, or mixtures of the isomers can be obtained. Conversely, it is also possible by heating the mixture of isomers to produce a pure isomer, usually the one which is more stable thermodynamically.

Similarly, racemic mixtures can be produced which can be converted by conventional means into single racemate pairs of optical isomers and, if desired, thereafter separated into a pure optical isomer.

Mixtures of compounds of Formulae Ia and lb can be separated in a conventional manner on the basis of their different solubilities, optionally also by chromatographical methods.

The compounds of Formula I can be converted into their acid addition salts with an acid in the usual manner. For this reaction, those acids are suitable which yield physiologically acceptable salts. It is possible to employ organic and inorganic acids, such as, e.g., aliphatic, alicyclic, araliphatic, aromatic, or heterocyclic, monoor polybasic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, oxalic acid, malonic acid, lactic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, tartaric acid, malic acid, aminocarboxylic acids, sulfamic acid, benzoic acid, salicylic acid, phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nucotinic acid, isonicotinic acid, methanesulfonic acid, ethane-disulfonic acid, B-hydroxyethanesulfonic acid, p-toluenesulfonic acid, naphthalene-, monoand -disulfonic acids, sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, or phosphoric acids, such as orthophosphoric acid. Other acids can be employed to produce acid addition salts for isolation, characterization and/or purification purposes.

The novel compounds of this invention can be employed in mixture with conventional pharmaceutical excepients. Carrier substances can be such organic or inorganic substances suitable for parenteral, enteral, or topical application, and which, of course, do not deleteriously react with the novel compounds, such as, for

example, water, vegetable oils, polyethylene glycols, glycerol, gelatin, lactose, amylose, corn starch, potato starch, magnesium stearate, talc, Vaseline, cholesterol, etc.

For parenteral application, particularly suitable are solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, Ampoules are convenient unit dosages.

For enteral application, particularly suitable are tablets or dragees which are also characterized by talc and/or a carbohydrate carrier or binder or the like, the carbohydrate carrier being preferably lactose and/or corn starch and/or potato starch. A syrup or the like can also be used wherein a sweetened vehicle is employed.

The compounds of this invention are generally administered to mammals in a dosage of 2-100 mg per dosage unit in mixture with l-5,000 mg of a solid, liquid or semi-liquid pharmaceutical carrier. The dosage per weight ratio is about 0.002 to 2 mg per kg of body weight, the dosage being increased or decreased according to the response of the mammal. Generally speaking, the compounds of this invention will be used in the same manner as known piperazines having CNS- depressant, e.g., tranquilizing activity.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The

following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

in the following examples, the temperatures are set forth in degrees Centigrade.

EXAMPLE 1 Under cooling, a solution of 2.5 g. of acetylhydrazine in a mixture of 20' ml. of ethanol and 1 ml. of concentrated HCl is poured into a solution of 10.1Ig. of 6-( N m-chlorophenylpiperazino)-2,4-hexanedione (obtainable from 6-bromo-2,4-hexanedione and N-m-chlorophenylpiperazine) in 200 ml. of ethanol, then heated for 4 hours to 60; the solvent is removed under vacuum, the residue is taken up in 100 ml. of 5% NaOH, extracted three times with 40 ml. of ether, the combined ether phases are dried with MgSO the ether is removed under vacuum, and in this way 1-acetyl- 3 5 )-[2-( N '-m-chlorophenylpiperazino )-ethyl] -5( 3 methylpyrazole is obtained; maleate, m.p. 145-147.

EXAMPLE 2 Under ice cooling, 3.53 ml. of acetyl chloride is added to 9.12 g. of 3(5)-[2-(N-mchlorophenylpiperazino )-ethyl ]-5( 3 )-methylpyrazole, dissolved in 100 ml. of absolute tetrahydrofuran and 4.75 ml. of anhydrous pyridine; the reaction mixture is agitated under the exclusion of water at room temperature for 2 days. The solvent is then distilled off, the residue is made alkaline with aqueous NaOH, extracted with ether, the ether phase dried over Na SO,, and the solvent distilled off, thus producing l-acetyl-3(5)-[2- (N-m-chlorophenylpiperazino)-ethyl]-5(3 )-methy1- pyrazole; maleate, m.p. l45l47.

EXAMPLE 3 5 g. of 3-[2-(N-m-chlorophenylpiperazino) ethyll- S-methylpyrazole is dissolved in 50 ml. of dry tetrahydrofuran. To this reaction mixture is added 1.25 g. of NaH, and the mixture is then boiled for 1 hour'under a nitrogen atmosphere. After cooling, 1.85 g. of N,N-dimethylcarbamoyl chloride is added thereto, the mixture refluxed for another hour, and then agitated for 2 days at room temperature. The reaction mixture is filtered, the filtrate concentrated by evaporation, taken up in ethanol, and precipitated with ethereal HCl. After recrystallization from ethanol/ether, dimethylaminocarbonyl-3- 2-( N '-mchlorophenylpiperazino)-ethyl]-5-methylpyrazo1e is obtained; hydrochloride, m.p. l98200. After evaporating the mother liquor, l-dimethylaminocarbonyl-5- [2-(N-m-chlorophenylpiperazino)-ethyl]-3- methylpyrazole. is produced; hydrochloridemonohydrate, m.p. 145-l47 (from isopropanol/ether).

acid anhydride is added dropwise thereto, the mixture is stirred for 2 days at room temperature, poured into an excess of ice water, and aqueous NaOH is added under stirring until a pH of about 8 has been attained. The mixture is extracted with ether, the ether phase is dried, the solvent is distilled off, and l-butyryl-3(5)-[2- (N -m-tolylpiperazino )-ethyl]-5 3 )-methylpyrazole is thus obtained; picrate, m.p. 200202.

EXAMPLE 5 A mixture of 6.2 g. of l-acetyl-3(5)-(2-chloroethyl)- 5(3)-methylpyrazole [obtainable by reacting 3-(2- chloroethyl)5-methylpyrazole with acetyl chloride], 6.5 g. of N-(m-chlorophenyl)-piperazine, 5 g. of anhydrous K CO and 100 ml. of dry dimethyl-formamide is agitated for '24 hours at lO-1l0; filtered after cooling; the solvent is distilled off, the residue taken up in a small amount of ethanol, mixed with an excess of ethanolic maleic acid, allowed to stand for 2 hours at 0, and the thus-separated crystals are vacuum-filtered, thus obtaining l-acetyl-3(5 )-[2-( N-mchlorophenylpiperazino)-ethyl]-5( 3 )-methylpyrazole maleate, m.p. l45l47.

EXAMPLE 6 A mixture of 9.7 g. of l-p-aminobenzoyl-3(5)-(2- bromoethyl)-5(3)-methylpyrazole [obtainable by reacting 3-(2-bromoethyl)-5-methylpyrazole with benzoyl bromide] and 5.9 g. of N-(m-tolyl)-piperazine is refluxed for 32 hours in 120 ml. of dry pyridine; the solvent is distilled off and the residue taken up in dry ether, filtered, the filtrate saturated with dry HCl gas, and the mixture allowed to stand for 3 hours at 0. The thus-separated crystals are vacuum filtered; in this way, l-p-aminobenzoyl-3 5 H 2-( N '-m-tolylpiperazino ethyl]-5(3)-methylpyrazole hydrochloride is obtained, softening starting with 200.

EXAMPLE 7 Analogously to Example 2, with the use of the follow-- ing starting compounds:

3-[ 2-( N '-phenylpiperazino )-ethyl ]-5-methylpyrazole 3-[ 2-( N -o-tolylpiperazino )-ethyl]-5-methylpyrazole 3-[ 2-(N'-m-tolylpiperazino)-ethyl1-5- methylpyrazole 3-[ 2-( N -p-tolylpiperazino )-ethyl]-5-methylpyrazole 10 3-[2-(N'-m-fluorophenylpiperazino)-ethyl]-5- methylpyrazole 3-[2-(N-p-fluorophenylpiperazino)-ethyl1-5- methylpyrazole 3-[2-(N'-o-chlorophenylpiperazino)-ethyl]-5- methylpyrazole 3-[2-(N-p-chlorophenylpiperazio)-ethyl]-5- methylpyrazole 3-[2-(N-o-bromophenylpiperazino)-ethyl1-5- methylpyrazole 3-[2-(N-m-bromophenylpiperazino)-ethyl1-5- methylpyrazole 3-[2-(N-p-bromophenylpiperazino)-ethyl]-5- methylpyrazole 3-[2-(N'-o-iodophenylpiperazino)-ethyl]-5- methylpyrazole 3-[2-(N-meiodophenylpiperazino)-ethyl]-5- methylpyrazole 3-[2-(N'-p-iodophenylpiperazino)-ethyl]-5- methylpyrazole I 3-[2-(N-o-methoxyphenylpiperazino)-ethyl]-5 methylpyrazole 3-[2-(N'-m-methoxyphenylpiperazino)-ethyl]-5- methylpyrazole 3-[2-(N-p-methoxyphenylpiperazino)-ethyl]-5- methylpyrazole 3-[2-(N-o-ethoxyphenylpiperazino)-ethyl]-5- methylpyrazole 1 3-[2-(N-m-ethoxyphenylpiperazino)-ethyl]-5- methylpyrazole 3-[2-(N'-p-ethoxyphenylpiperazino)-ethyl]-5- methylpyrazole 3-[2-(N-o-trifluoromethylphenylpiperazino)-ethyl]- S-methylpyrazole 3-[ 2-( N -m-trifluoromethylphe nylpiperazino ethyl]-5-methylpyrazole 3-[2-(N-p-trifluoromethylphenylpiperazino)-ethyl]- S-methylpyrazole 3-{2-[N'-(2,4-dimethoityphenyD-piperazino]- ethyl}-5-methylpyrazole W 6,4-dimethoxyphenyl)-piperazmo] eth yl -5-methylpyrazole 3-{2-[N-(3T4,5-trimethoxyphenyD-pipraiino]- ethyl}-5-methylpyrazole, the following products are obtained by reaction with acetyl chloride:

1-acetyl-3(5 )-[2-(N '-phenylpiperazino )-ethyl]-5( 3 methylpyrazole l-acetyl-3(5 )-[2-( N -o-tolylpiperazino)-ethyl]-5( 3 methylpyrazole 1-acetyl-3(5)-[2-(N'-m-tolylpiperazino)-ethyl]- 5( 3 )-methylpyrazole 1-acetyl-3(5)-[2-(N'-p-tolylpiperazino)-ethyl]-5(3) methylpyrazole 1 -acetyl-3 5 2-( N -o-ethylphenylpiperazino)- ethyl]-5(3)-methylpyrazole v l-acetyl-3(5 )-[2-( N '-m-ethylphenylpiperazino ethyl]-5(3)-methylpyrazole l-acetyl-3 5 )-[2-( N -p-ethylphenylpiperazino)- ethyl ]-5 3 )-methylpyrazole l-acetyl-3 5 )-[2-( N -o-isopropylphenylpiperazino)- ethyl]5 3 )-methylpyrazole l-acetyl-3(5)-[2-(Nf-m-isopropylphenylpiperazino)- ethyl 1-5 3 )-methylpyrazole l-acetyl-3( 5 )-[2-( N '-p-isopropylphenylpiperazino)- ethyl]-5 3 )-methylpyrazole and the ether is distilled off. The product thus obtained in l-butyryl-3(5)-[2-(N'-m-tolylpiperazino)-ethyl]- 5(3)-methylpyrazole; picrate, m.p. 200-202.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. 1

What is claimed is: I

1. A member of the group consisting of a compound of the formula Q-CH CHy-N N-Ar wherein Ar is phenyl or phenyl mono-, di or trisub s ti tuted by methyl, ethyl, isopropyl, methoxy, ethoxy, halogen, or mono-substituted trifluoromethyl, and Q is the corresponding compound wherein Q is NCOR CH: N

amino, alkyl in each instance being of one to three carbon atoms, a mixture of the two compounds, and the physiologically acceptable acid addition salts thereof.

' chlorophenylpiperazino)-ethyl]-3-methylpyrazole.

6. The compound of claim 3, l-butyryl-3-[2-(N'-mchlorophenylpiperazino )-ethyl ]-5-methylpyrazole.

7. The compound of claim 3, l-butyryl-5-[2-(N'-mchlorophenylpiperazino )-ethyl ]-3-methylpyrazole.

8. The compound of claim 2, l-butyryl-3-[2-(N'-mtolylpiperazino)-ethylJ-S-methylpyrazole.

9. The compound of claim 2, l-butyryl-5-[2-(N-mtolylpiperazino )-ethyl ]-3 -methylpyrazole.

10. The compound of claim 3, l-nonanoyl-3-[2-(N- m-chlorophenylpiperazino )-ethyl ]-5-methylpyrazole.

11. The compound of claim 3, l-nonanoyl-S-[Z-(N m-chlorophenylpiperazino)-ethyl]-3-methylpyrazole.

12. The compound of claim 3, l-benzoyl-3-[2-(N-mchlorophenylpiperazino)-ehtyl]-5-methylpyrazole.

13. The compound of claim 3, l-benzoyl-5-[2-(N'-mchlorophenylpiperazino)-ethyl]-3-methylpyrazole.

14. The compound of claim 3, l-p-aminobenzoyl-IB- [2-(N'-m-chlorophenylpiperazino)-ethyl]-5 -methylpyrazole.

15. The compound of claim 3, l-p-aminobenzoyl-5- [2-(N' m-chlorophenylpiperazino)-ethyl]-3- methylpyrazole.

16. The compound of claim 3, trimethoxybenzoyl )-3- 2-( N -mchlorophenylpiperazino)-ethyl]-5-methy1pyrazole.

17. The compound of claim 3, 1-(3,4,5- trimethoxybenzoyl )-5'- 2-( N -mchlorophenylpiperazino)-ethyl]-3-methylpyrazole. 

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA
 2. A compound of claim 1 wherein R is alkyl of up to 10 carbon atoms.
 3. A compound of claim 1 wherein Ar is phenyl or phenyl substituted by halo or alkyl of one to three carbon atoms.
 4. The compound of claim 3, 1-acetyl-3-(2-(N''-m-chlorophenylpiperazino)-ethyl)-5-methylpyrazole.
 5. The compound of claim 3, 1-acetyl-5-(2-(N''-m-chlorophenylpiperazino)-ethyl)-3-methylpyrazole.
 6. The compound of claim 3, 1-butyryl-3-(2-(N''-m-chlorophenylpiperazino)-ethyl)-5-methylpyrazole.
 7. The compound of claim 3, 1-butyryl-5-(2-(N''-m-chlorophenylpiperazino)-ethyl)-3-methylpyrazole.
 8. The compound of claim 2, 1-butyryl-3-(2-(N''-m-tolylpiperazino)-ethyl)-5-methylpyrazole.
 9. The compound of claim 2, 1-butyryl-5-(2-(N''-m-tolylpiperazino)-ethyl)-3-methylpyrazole.
 10. The compound of claim 3, 1-nonanoyl-3-(2-(N''-m-chlorophenylpiperazino)-ethyl)-5-methylpyrazole.
 11. The compound of claim 3, 1-nonanoyl-5-(2-(N''-m-chlorophenylpiperazino)-ethyl)-3-methylpyrazole.
 12. The compound of claim 3, 1-benzoyl-3-(2-(N''-m-chlorophenylpiperazino)-ehtyl)-5-methylpyrazole.
 13. The compound of claim 3, 1-benzoyl-5-(2-(N''-m-chlorophenylpiperazino)-ethyl)-3-methylpyrazole.
 14. The compound of claim 3, 1-p-aminobenzoyl-3-(2-(N''-m-chlorophenylpiperazino)-ethyl)-5 -methylpyrazole.
 15. The compound of claim 3, 1-p-aminobenzoyl-5-(2-(N''-m-chlorophenylpiperazino)-ethyl)-3-methylpyrazole.
 16. The compound of claim 3, 1-(3,4,5-trimethoxybenzoyl)-3-(2-(N''-m-chlorophenylpiperazino)-ethyl)-5 -methylpyrazole.
 17. The compound of claim 3, 1-(3,4,5-trimethoxybenzoyl)-5-(2-(N''-m-chlorophenylpiperazino)-ethyl)-3 -methylpyrazole. 